Postoperative high-sensitivity troponin T predicts 1-year mortality and days alive and out of hospital after orthotopic heart transplantation

Background Orthotopic heart transplantation (HTX) is the gold standard to treat end-stage heart failure. Numerous risk stratification tools have been developed in the past years. However, their clinical utility is limited by their poor discriminative ability. High sensitivity troponin T (hsTnT) is the most specific biomarker to detect myocardial cell injury. However, its prognostic relevance after HTX is not fully elucidated. Thus, this study evaluated the predictive value of postoperative hsTnT for 1-year survival and days alive and out of hospital (DAOH) after HTX. Methods This retrospective cohort study included patients who underwent HTX at the University Hospital Duesseldorf, Germany between 2011 and 2021. The main exposure was hsTnT concentration at 48 h after HTX. The primary endpoints were mortality and DAOH within 1 year after surgery. Receiver operating characteristic (ROC) curve analysis, logistic regression model and linear regression with adjustment for risk index for mortality prediction after cardiac transplantation (IMPACT) were performed. Results Out of 231 patients screened, 212 were included into analysis (mean age 55 ± 11 years, 73% male). One-year mortality was 19.7% (40 patients) and median DAOH was 298 days (229–322). ROC analysis revealed strongest discrimination for mortality by hsTnT at 48 h after HTX [AUC = 0.79 95% CI 0.71–0.87]. According to Youden Index, the cutoff for hsTnT at 48 h and mortality was 1640 ng/l. After adjustment for IMPACT score multivariate logistic and linear regression showed independent associations between hsTnT and mortality/DAOH with odds ratio of 8.10 [95%CI 2.99–21.89] and unstandardized regression coefficient of −1.54 [95%CI −2.02 to −1.06], respectively. Conclusion Postoperative hsTnT might be suitable as an early prognostic marker after HTX and is independently associated with 1-year mortality and poor DAOH. Supplementary Information The online version contains supplementary material available at 10.1186/s40001-022-00978-4.


Introduction
Orthotopic heart transplantation (HTX) is still the gold standard therapy for end-stage heart failure. Unfortunately, there is an ongoing donor shortage which limits the number of HTX and leads to an increasing number of patients on HTX waiting lists [1]. In addition, the treatment of end-stage heart failure is continuously improving so that the patients undergoing HTX are getting older and have more comorbidities with an increased risk for postoperative complications [2,3]. To optimize perioperative risk stratification and early re-estimation of risk, the development of risk prediction models and the identification of perioperative prognostic factors became more and more important [4,5,6]. Numerous risk stratification tools have been developed in the past years, but their clinical use is often limited by insufficient predictive values [5]. In this context, the Index for Mortality Prediction After Cardiac Transplantation (IMPACT) score was introduced as validated tool for prediction of 1-year mortality after HTX [7,8]. However, some studies report poor-to-moderate discrimination for mortality in their cohorts [9][10][11].
Previously biomarkers were established as another possibility to support perioperative stratification and early re-estimation of risk. A sensitive biomarker for myocardial cell injury is high-sensitivity troponin T (hsTnT) [12]. Postoperative troponin release has been investigated extensively in cardiac and non-cardiac surgery and is associated with adverse events [13,14,15]. Recently, Devereaux et al. investigated the prognostic value of high-sensitivity troponin I (hsTnI) in patients undergoing cardiac surgery and showed that levels of hsTnI were independently associated with mortality [16]. The role of hsTnT as a prognostic factor after HTX, however, is not clear and recent literature is ambiguous [17]. Therefore, we conducted this analysis to evaluate whether hsTnT is a suitable marker for risk stratification and prognosis after HTX.

Methods
This retrospective single-center cohort study was approved by the University of Duesseldorf 's ethics committee (reference number: 4567) and complies with the International Society for Heart and Lung Transplantation (ISHLT) ethics statement. Data were extracted from the local prospective HTX database. All patients had given written informed consent to be registered in this database. Reporting of this work corresponds to the "Strengthening the Reporting of Observational Studies in Epidemiology" (STROBE) guidelines [18].

Patient population
All patients aged ≥ 18 years who underwent HTX at the University Hospital Duesseldorf, Germany, in a time period from September 2010 to August 2021 were considered for inclusion. Patients with missing data regarding survival, DAOH and hsTnT measurements, as well as patients without completed 1-year follow-up were excluded from analysis. In all patients HTX was conducted using bicaval technique and traditional cold storage was used for donor organ preservation.

High-sensitivity troponin T measurements
Main exposure was postoperative hsTnT measured in ng/L after HTX at different time points. At our institution hsTnT is routinely measured preoperatively, within the first 12 h, day 1, day 2 and day 3 after HTX. Measurements were performed in the central laboratory of the University hospital Duesseldorf.

IMPACT score calculation
The risk index for mortality prediction after cardiac transplantation (IMPACT) is a score validated to predict 1-year mortality after HTX from preoperative recipient risk factors. This score assigns varying points for 10 variables: age, serum bilirubin, creatinine clearance, dialysis, sex, heart failure etiology, preoperative infection, race, circulatory support and type of ventricular assist device. The score was calculated for each HTX patient as described before with a maximum of 50 points [7,8].

Outcomes
The primary outcome of this study was mortality during the first year after HTX. Days alive and out of hospital (DAOH) at 1 year after HTX was the secondary endpoint of this study. Calculation of DAOH was conducted by summing up all days of hospitalization in the first year after HTX and subtracting them from 365 days, as described before [19][20][21]. In case of mortality, the number of days the patient did not survive and of days spent in hospital were subtracted from 365 days.

Statistical analysis
Statistical analysis was performed using IBM SPSS © software version 25.0 (Armonk, NY, USA), GraphPad Prism © version 8.02 (La Jolla, California, USA), MedCalc ® Statistical Software version 20.114 (MedCalc Software Ltd, Ostend, Belgium) and R Statistical Software (v4.1.2; R Core Team 2021). Patients characteristics with continuous variables were presented as mean ± standard deviation (SD) or as median and interquartile ranges (IQR, 25-75%), as appropriate. Categorical variables were presented as numbers (n) with corresponding percentages (%) in brackets. Fisher's exact test or unpaired t-tests 1-year mortality, a decision curve analysis was performed for both models. For analysis of DAOH patients were classified by hsTnT cutoff. DAOH was compared using non-parametric Mann-Whitney U test. Association of continuous hsTnT elevation per 100 ng/L with DAOH was adjusted by the continuous IMPACT score using multivariable linear regression. For all statistical tests, a p < 0.05 was considered significant.

Study cohort and characteristics
In total 231 patients underwent HTX at the University Hospital Duesseldorf during the time period of September 2010 and December 2021. Thereof, 19 (8%) patients had to be excluded according to the exclusion criteria. Among the 212 included patients, mean age was 55 ± 11 years and 155 (73%) were male. During first year after HTX, 40 patients (19%) died. Causes of death were: graft dysfunction (7 patients), septic shock (9 patients), major bleeding complications (6 patients with intracranial hemorrhage, 1 patient with gastrointestinal bleeding, 1 patient with ECMO cannulation site bleeding), bowel ischemia (3 patients), cerebral hypoxia (3 patients) and unknown causes (10 patients who died out of hospital). Overall median DAOH was 298 days (229-322). Detailed patient characteristics for survivors and non-survivors are presented in Table 1 (Additional file 1: Figure S1, Table 1).

HsTnT levels of survivors and non-survivors after HTX
Baseline levels of hsTnT did not differ significantly between survivors and non-survivors. In contrast, postoperative hsTnT levels were significantly higher in patients who died as compared to survivors at 12 h, 24 h, 48 h and 72 h after HTX. Detailed results are presented in Fig. 1.

Discussion
The present study suggested that early hsTnT levels at 48 h after HTX are independently associated with mortality and DAOH after HTX. Moreover, this study showed that the addition of hsTnT improved risk prediction for mortality and DAOH over IMPACT score.
Referring to the current literature, the prognostic value of troponin after HTX is underexplored. A recent systematic review by Liu and colleagues identified only three studies including a total of 372 patients that investigated the association between elevated troponin levels and mortality. As these studies revealed significant heterogeneities, the authors decided not to perform a metaanalysis [17]. Labarrere et al. investigated the value of persistent troponin I (TnI) levels in 110 HTX patients during first year after HTX. They found that persistent TnI levels greater than 0.5 ng/ml were associated with development of coronary artery disease and graft failure. However, as patients were only included if they had survived the first year after HTX, association of postoperatively elevated TnI and early mortality was not investigated [22]. Another study investigated the prognostic value of postoperative hsTnT for 1-year mortality in 141 HTX patients. They identified that elevated hsTnT levels at 6 weeks after HTX were highly associated with 1-year mortality. Again, association of early postoperative levels of hsTnT was not investigated by the authors [23]. The last study by Franeková et al. demonstrated an association of hsTnT levels at 10 days after HTX and 1-year mortality [24]. However, an earlier postoperative assessment of risk might be favorable as it might change clinical practice for patients at risk. Postoperative troponin release has been extensively studied in non-cardiac surgery before [25,26]. In these studies, early postoperative troponin elevation above the upper limit of normal was associated with major adverse events like mortality. In cardiac surgery however, this upper limit of normal troponin concentration is frequently exceeded by myocardial trauma due to surgery, with not necessarily higher risk for mortality [13]. Therefore, Devereaux et al. defined new cutoffs for association of troponin and 30-day mortality after cardiac surgery corresponding with an hsTnI level 218 times the upper reference limit [16]. Our recent study now adds data for association of early hsTnT with 1-year mortality after HTX. Patients who died within the first year after HTX had significantly higher troponin values at each timepoint of measurement. These findings were independently associated when adjusted for the IMPACT score. IMPACT score showed weak-to-moderate association with 1-year mortality in our cohort. This goes in line with previous reports, describing similar AUC in ROC analysis [9,11]. Addition of hsTnT level at 48 h improved the discrimination ability of IMPACT score. The net benefit using the combined model was also higher to identify patients at risk for 1-year mortality. Recently, similar risk prediction models and decision curve analyses for mortality were presented as effective to guide palliative care consultation [27,28]. Additionally, hsTnT levels were independently associated with low DAOH. This is an important finding, as this complements the current knowledge on more patient-centered outcomes in the field of end-stage heart failure and HTX surgery [21,29,30].
In the Eurotransplant area, the responsible parties discuss the implementation of a cardiac allocation score (CAS) which is supposed to optimize the allocation of the limited donor organs. In the lung transplantation setting, a similar score already exists (Lung allocation score (LAS)) which is also used to prioritize waiting list candidates 12 years and older based on a combination of waitlist urgency and post-transplant survival. Based on the data of this study, postoperative hsTnT may also be included into such a score for early re-estimation of postoperative risk and prognosis. Further studies should focus on potential interventions depending on hsTnT values that might be able to prevent complications and finally to reduce mortality after HTX. These may include intensified monitoring or standardized protocols for strict follow-up of these patients.

Strengths and limitations
Strengths of the presented data include first, standardized troponin measurement at multiple time points with high data completeness; second, complete 12-month follow-up. Further, we did not only address mortality but also DOAH, a more patient-centered endpoint to quantify life impact [19]. We are aware of the following limitations. First, as a single-center study, sample size and number of events was limited. However, only 2 variables (troponin and IMPACT) were included into the logistic model that can therefore be considered robust. Second, we cannot exclude that any external hospitalization took place. However, HTX patients are very closely connected to our center so that we consider the risk of misclassification bias was very limited. Further, although DAOH is a measure of life impact, we did not collect data on quality of life, another relevant patient-centered outcome. Finally, we chose hsTnT at 48 h after HTX as primary biomarker for our analysis as it showed the numerically strongest discrimination for 1-year mortality. However, Fig. 4 Decision curves for different models of risk prediction after HTX. The figure shows a decision curve analysis for mortality prediction model with IMPACT score (turquoise) and IMPACT score with hsTnT (purple). The x-axis shows the threshold probability for 1-year mortality while the y-axis shows the net benefit of the models. Beyond a threshold of 5% the combined model of IMPACT and hsTnT shows the greatest net benefit. The red line depicts a model in which all patients would be treated and the green line represents a model in which none patient will be treated ROC-AUC did not significantly differ from values at 24 h and 72 h. In this context an earlier timepoint like 24 h after HTX might be favorable for early re-estimation of postoperative risk in the clinical setting. Therefore, optimal cutoff and sampling time point should be investigated in a larger cohort.
The generalizability of these findings may be hampered by the single-center design. However, characteristics such as 1-year mortality were in line with the current literature.

Conclusion
Early hsTnT levels after HTX surgery are independently associated with poor 1-year survival and reduced DAOH. Therefore, early hsTnT concentrations might be useful for early risk reassessment to tailor postoperative therapy or decision-making in the intensive care unit.